Elucadation of genetic disorders and molecular pathogenesis in inherited bradyarrhythmia due to the abnormalities in genes encoding sarcomere components

• Project/Area Number: 26860572
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Nagasaki University
• Principal Investigator: ISHIKAWA Taisuke 長崎大学, 医歯薬学総合研究科(医学系), 助教 (60708692)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 徐脈 / 不整脈 / 遺伝子 / 変異 / 遺伝子解析 / 心房 / 興奮伝導 / 次世代シークエンサー / 遺伝子異常 / ターゲットシークエンス / チャネル / サルコメア / 遺伝子変異 / 洞不全症候群 / 心房性不整脈

Outline of Final Research Achievements

The etiology of familial suprabventricular bradyarrhythmia without basal heart disorders is partly due to genetic disorders. The aim of the study is to elucidate the responsible genes and mutations in the patients susceptible for genetic etiology. By using next generation sequencer to screen mutations for 200 genes that are preferentially expressed in the heart, we identified responsible genes and mutations in approximately 40% of cases (12 probands) with unknown etiology, including two novel responsible genes for sick sinus syndrome. In combination with the functional assay by using heterologous overexpression system, we determined 11 mutations in 6 genes as genetic disorders underlysing familial supraventricular bradyarrhythmia.

Research Products

• [Journal Article] Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. (2016)
  • Author(s): Koizumi A, Sasano T, Kimura W, Miyamoto Y, Aiba T, Ishikawa T, Nogami A, Fukamizu S, Sakurada H, Takahashi Y, Nakamura H, Ishikura T, Koseki H, Arimura T, Kimura A, Hirao K, Isobe M, Shimizu W, Miura N, Furukawa T.
  • Journal Title: European Heart Journal. Volume: 37 (18) Issue: 18 Pages: 1469-1475
  • DOI: 10.1093/eurheartj/ehv449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inherited bradyarrhythmia: A diverse genetic background. (2016)
  • Author(s): Ishikawa T, Tsuji Y, Makita N
  • Journal Title: Journal of Arrhythmia Volume: 印刷中 Issue: 5 Pages: 352-358
  • DOI: 10.1016/j.joa.2015.09.009
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A novel mutation in alpha-myosin heavy chain gene is associated with sick sinus syndrome (2015)
  • Author(s): Ishikawa T, Jou CJ, Nogami A, Kowase S, Arrington CB, Barnett SM, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N
  • Journal Title: Circ Arrhythm Electrophysiol Volume: 8 Issue: 2 Pages: 400-108
  • DOI: 10.1161/circep.114.002534
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome. (2015)
  • Author(s): Harrell DT, Ashihara T, Ishikawa T, et al.
  • Journal Title: International Journal of Cardiology. Volume: 190 Pages: 393-402
  • DOI: 10.1016/j.ijcard.2015.04.090
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 徐脈性疾患と分子遺伝学 (2015)
  • Author(s): 石川泰輔 蒔田直昌
  • Journal Title: 循環器内科 Volume: 4 Pages: 360-365
• [Journal Article] Molecular mechanisms of heart failure progression associated with implantable cardioverter-defibrillator shocks for ventricular tachyarrhythmias. (2014)
  • Author(s): Tsuji Y, Ishikawa T, Makita N.
  • Journal Title: J Arrhythmia. Volume: 30 Issue: 4 Pages: 235-241
  • DOI: 10.1016/j.joa.2014.04.003
  • Peer Reviewed
• [Journal Article] Novel calmodulin mutations associated with congenital arrhythmia susceptibility. (2014)
  • Author(s): Makita N, Tsuji Y（39人中21番目）et al
  • Journal Title: Circ Cardiovasc Genet. Volume: 7 Issue: 4 Pages: 466-474
  • DOI: 10.1161/circgenetics.113.000459
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. (2014)
  • Author(s): Abe K, Machida T, Sumitomo N, Yamamoto H, Ohkubo K, Watanabe I, Makiyama T, Fukae S, Kohno M, Harrell DT, Ishikawa T, Tsuji Y, Nogami A, Watabe T, Oginosawa Y, Abe H, Maemura K, Motomura H, Makita N.
  • Journal Title: Circ Arrhythm Electrophysiol Volume: in press Issue: 3 Pages: 511-517
  • DOI: 10.1161/circep.113.001340
  • NAID: 120006986434
  • Peer Reviewed
• [Presentation] Naチャネル遺伝子のバリエーションと致死性不整脈の罹患性との関連 (2016)
  • Author(s): 蒔田直昌 石川泰輔
  • Organizer: 第93回日本生理学会大会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2016-03-23
  • Int'l Joint Research
• [Presentation] Dose-Sensitive Relationship of an SCN10A Pore Mutation and Enhancer SNPs Identified in a Brugada Syndrome Family with Different Expressivity (2016)
  • Author(s): Ishikawa, T. Ohkubo, K. Yamaguchi, R. Harrell, D. T. Tsuji, Y. Watanabe, I. Makita, N.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際会議場(宮城県・仙台市）
  • Year and Date: 2016-03-18
  • Int'l Joint Research
• [Presentation] 家族性心臓伝導障害に同定されたコネキシン遺伝子変異とその機能異常 (2015)
  • Author(s): 石川泰輔 西井明子 斎藤加代子 三嶋博之 大槻早紀 稲田慎 ダニエルハーレル 辻幸臣 中沢一雄 吉浦孝一郎 萩原誠久 蒔田直昌
  • Organizer: 心血管膜輸送研究会2015
  • Place of Presentation: 生理学研究所（愛知県・岡崎市）
  • Year and Date: 2015-10-30
• [Presentation] 乳幼児突然死症例に対する次世代シークエンサーを用いた脂肪酸代謝異常の遺伝子解析 (2015)
  • Author(s): 大崎琢弥 山本琢磨 石川泰輔 三嶋博之 深堀友希 梅原敬弘 村瀬壮彦 吉浦孝一郎 蒔田直昌 池松和哉
  • Organizer: 日本法医学会学術九州地方集会
  • Place of Presentation: 宮崎大学（宮崎県・宮崎市）
  • Year and Date: 2015-10-16
• [Presentation] 重症不整脈を伴うQT延長症候群の新規原因遺伝子CALM2の同定 (2015)
  • Author(s): 石川泰輔 須田憲治 本村秀樹 山本雄大 牧山武 ダニエルハーレル 辻幸臣 蒔田直昌
  • Organizer: 第66回西日本生理学会
  • Place of Presentation: 久留米大学（福岡県・久留米市）
  • Year and Date: 2015-10-10
• [Presentation] Meta-analysis of Short QT Syndrome discloses genotype-dependent clinical characteristics in age of manifestation and arrhythmia complications. (2015)
  • Author(s): Harrell, D. T. Ashihara, T. Ishikawa, T. Mazzanti, A. Takahashi, K. Oginosawa, Y. Abe, H. Maemura, K. Sumitomo, N. Uno, K. Takano, M. Priori, S. G. Makita, N.
  • Organizer: 第30回日本不整脈学会学術大会・第32回日本心電学会学術集会
  • Place of Presentation: 京都国際会議場（京都府・京都市）
  • Year and Date: 2015-07-28
  • Int'l Joint Research
• [Presentation] Dose-Sensitive Relationship of an SCN10A Pore Mutation and Enhancer SNPS Identified in a Brugada Syndrome Family with Different Expressivity (2015)
  • Author(s): Ishikawa, T. Ohkubo, K. Yamaguchi, R. Harrell, D. T. Tsuji, Y. Watanabe, I. Makita, N.
  • Organizer: Heart Rhythm Society
  • Place of Presentation: ﾎﾞｽﾄﾝ（米国）
  • Year and Date: 2015-05-15
  • Int'l Joint Research
• [Presentation] Emerging link between genetic variations of sodium channels and susceptibility to lethal arrhythmias. (2015)
  • Author(s): Makita N, Ishikawa T, Schott JJ, Bezzina CR.
  • Organizer: 第88回日本薬理学会
  • Place of Presentation: 名古屋市、名古屋国際会議場
  • Year and Date: 2015-03-19
  • Invited
• [Presentation] A novel cardiac alpha-myosin heavy chain (MYH6) mutation impairing sarcomere structure responsible for familial sick sinus syndrome (2014)
  • Author(s): Ishikawa T, Nogami A, Kowase S, Harrell D, Tsuji Y, Arimura T, Kimura A, Makita N.
  • Organizer: European Society of Cardiology.
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-09-02
• [Presentation] 不整脈の新規病因解明を目指す全エクソン解析とiPS技術のハイブリッドアプローチ (2014)
  • Author(s): 石川泰輔, 牧山武, 蒔田直昌
  • Organizer: 新学術研究領域「統合的多階層生体機能学領域の確立とその応用」
  • Place of Presentation: 秋田市、秋田大学
  • Year and Date: 2014-08-05
• [Presentation] Electrical Storm in Inherited Arrhythmia Syndromes. (2014)
  • Author(s): Tsuji Y, Ishikawa T, Makita N.
  • Organizer: 第29回日本不整脈学会・第31回日本心電学会合同学術大会.
  • Place of Presentation: 東京都港区、ザ・プリンスパークタワー東京
  • Year and Date: 2014-07-23
• [Presentation] A Novel Cardiac a-Myosin Heavy Chain (MYH6) Mutation Associated with Familial Sick Sinus Syndrome Altering Sarcomeric Organization. (2014)
  • Author(s): Ishikawa T, Nogami A, Kowase S, Arimura T, Kimura A, Makita N.
  • Organizer: 第29回日本不整脈学会・第31回日本心電学会合同学術大会.
  • Place of Presentation: 東京都港区、ザ・プリンスパークタワー東京
  • Year and Date: 2014-07-23
• [Presentation] A Novel Cardiac a-Myosin Heavy Chain (MYH6) Mutation Associated with Familial Sick Sinus Syndrome Altering Sarcomeric Organization. (2014)
  • Author(s): Ishikawa T, Nogami A, Kowase S, Arimura T, Kimura A, Makita N.
  • Organizer: 35th Annual Scientific Sessions,Heart Rhythm.
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-05-10
• [Book] 不整脈症候群－遺伝子変異から不整脈治療を捉えるー (2015)
  • Author(s): 池田隆徳 清水渉 高橋尚彦
  • Publisher: 南江堂
• [Book] 不整脈症候群－遺伝子変異から不整脈治療を捉える (2015)
  • Author(s): 石川泰輔、蒔田直昌
  • Total Pages: 196
  • Publisher: 南江堂